# Metabolic imprinting of dendritic cell fate and function in tissues

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $367,389

## Abstract

ABSTRACT
Dendritic cells (DCs) play a central role in sensing pathogens and tuning immune responses.
Functionally distinct subsets of DCs can stimulate different types of immune responses, but DCs
also display functional plasticity in response to microbial stimuli or signals from the tissue
microenvironment. However, it is now clear that DCs sense not just microbial stimuli, but also
various stress signals (e.g. amino acid starvation), through ancient stress sensing mechanisms,
leading to a metabolic reprogramming of their function. In particular our recent work has
revealed fundamental roles for two major amino acid sensors GCN2 and mTOR, in
programming DCs to modulate adaptive immunity and inflammation. We have shown that GCN2
plays a role in programming DCs to respond to viral vaccination, and in controlling intestinal
inflammation by promoting autophagy and suppressing inflammasome activation in gut APCs
and epithelial cells. Furthermore, our recent data demonstrates that GCN2 regulates allergic
inflammation in the lung. In addition to these effects of GCN2, we have recently shown that
mTOR regulates developmental fate of DCs and alveolar macrophages (AMs) in the lung, and
reprograms their metabolic state to modulate the outcome of allergic inflammation. In the
following aims, we will determine the mechanisms of this metabolic imprinting.
Aim 1: To determine the mechanisms by which mTOR controls the homeostasis and
function of lung DCs and AMs in the steady state and during allergic inflammation. Our
recent work demonstrates that in mice in which mTOR is genetically ablated in CD11c+ cells
(mTORAPC mice): (i) CD103+ DCs and AMs in the lung are greatly reduced in number, in the
steady state. (ii) Although the lung CD11c+CD11b+ DCs were numerically unaffected, they were
skewed in their transcriptional identity towards the macrophage/monocytic profile. (iii) Lung
allergic Th2 inflammation was skewed toward the Th17/neutrophilic phenotype. In the present
aim, we will investigate the mechanisms underlying these effects, and investigate the potential
role of 4E-BP3 dependent translational control, lipid metabolism and epigenetic reprograming in
mediating the effects of mTOR signaling.
Aim 2: To determine the mechanisms by which GCN2 regulates Th2 responses and
allergic inflammation. Our preliminary data demonstrate that GCN2 knockout mice display
markedly reduced allergic inflammation in the lung. In this aim we will determine the molecular
mechanisms underlying this effect. The successful completion of these aims will yield rich
mechanistic insights about metabolic imprinting of DC fate and function.

## Key facts

- **NIH application ID:** 10331303
- **Project number:** 5R01AI048638-22
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** BALI PULENDRAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,389
- **Award type:** 5
- **Project period:** 2001-03-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10331303

## Citation

> US National Institutes of Health, RePORTER application 10331303, Metabolic imprinting of dendritic cell fate and function in tissues (5R01AI048638-22). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10331303. Licensed CC0.

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